2. Academic Validation
  3. Suppressive Effects of the Site 1 Protease (S1P) Inhibitor, PF-429242, on Dengue Virus Propagation

Suppressive Effects of the Site 1 Protease (S1P) Inhibitor, PF-429242, on Dengue Virus Propagation

  • Viruses. 2016 Feb 10;8(2):46. doi: 10.3390/v8020046.
Leo Uchida 1,  Shuzo Urata 2,  Gianne Eduard L Ulanday 3 4,  Yuki Takamatsu 5,  Jiro Yasuda 6 7,  Kouichi Morita 8 9,  Daisuke Hayasaka 10 11
Affiliations

Affiliations

  • 1 Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. uchidaleo@rakuno.ac.jp.
  • 2 Department of Emerging Infectious Disease, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. shuzourata@nagasaki-u.ac.jp.
  • 3 Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. ulanday@tm.nagasaki-u.ac.jp.
  • 4 Graduate school of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. ulanday@tm.nagasaki-u.ac.jp.
  • 5 Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. yuki.takamatsu@staff.uni-marburg.de.
  • 6 Department of Emerging Infectious Disease, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. j-yasuda@nagasaki-u.ac.jp.
  • 7 Leading graduate school program, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. j-yasuda@nagasaki-u.ac.jp.
  • 8 Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. moritak@nagasaki-u.ac.jp.
  • 9 Leading graduate school program, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. moritak@nagasaki-u.ac.jp.
  • 10 Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. hayasaka@nagasaki-u.ac.jp.
  • 11 Leading graduate school program, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. hayasaka@nagasaki-u.ac.jp.
PMID: 26875984 DOI: 10.3390/v8020046
Abstract

Dengue virus (DENV) Infection causes one of the most widespread mosquito-borne diseases in the world. Despite the great need, effective vaccines and practical Antiviral therapies are still under development. Intracellular lipid levels are regulated by sterol regulatory elements-binding proteins (SREBPs), which are activated by serine Protease, site 1 Protease (S1P). Small compound PF-429242 is known as a S1P inhibitor and the antivirus effects have been reported in some viruses. In this study, we examined the anti-DENV effects of PF-429242 using all four serotypes of DENV by several primate-derived cell lines. Moreover, emergence of drug-resistant DENV mutants was assessed by sequential passages with the drug. DENV dependency on intracellular lipids during their Infection was also evaluated by adding extracellular lipids. The addition of PF-429242 showed suppression of viral propagation in all DENV serotypes. We showed that drug-resistant DENV mutants are unlikely to emerge after five times sequential passages through treatment with PF-429242. Although the levels of intracellular Cholesterol and lipid droplets were reduced by PF-429242, viral propagations were not recovered by addition of exogenous Cholesterol or fatty acids, indicating that the reduction of LD and Cholesterol caused by PF-429242 treatment is not related to its mechanism of action against DENV propagation. Our results suggest that PF-429242 is a promising candidate for an anti-DENV agent.

Keywords

PF-429242; S1P; SREBPs; antivirus drug; dengue virus.

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